Human immunodeficiency virus (HIV) is the etiologic agent of acquired immunodeficiency syndrome (AIDS), a fatal disease characterized by profound immunosuppression, opportunistic infections, and neuropathies. Although only a small fraction of circulating lymphocytes are infected with the virus, there is a marked loss of T cells bearing the virus receptor CD4. The depletion of CD4+-T cells appears to contribute significantly to the immunosuppression associated with AIDS. Syncytium formation resulting from HIV-induced cell fusion has been shown to be the primary cytopathic effect of the virus in vitro and has been postulated to account for the loss of CD4+-T cells in vivo. CD4 through its interaction with the HIV envelope glycoprotein gp120 plays an important role in syncytium formation.
Although the CD4 receptor appears to play a significant role in the etiology of AIDS, several observations suggest that molecules on the surface of uninfected cells other than CD4 are also involved in HIV-induced cell fusion. First, fusion of HIV-infected cells to uninfected cells does not correlate with CD4-density on the surface of the uninfected cells. In addition, whereas transfection of non-lymphoid human cells with CD4 receptors renders such cells capable of fusion to HIV-infected cells, this is not true for CD4-transfected mouse cells. Finally, there is a disparity in the capacity of sera from AIDS patients to block binding of HIV particles to CD4+-cells and the capacity of the same sera to block fusion of HIV-infected cells to CD4+-uninfected cells.
CD4 interacts directly with class II major histocompatibility complex (MHC) molecules in class II MHC-restricted T helper cell responses. The involvement of the leukocyte adhesion receptor (LAR) LFA-1, in such responses has been demonstrated using anti-LFA-1 monoclonal antibodies (mAb). Structural similarities between gp120 and class II MHC suggested that the binding of gp120 to CD4 may mimic the interaction between class II MHC molecules and CD4. By analogy, the role of LAR in HIV-mediated cell fusion was examined. In the present invention, a mAb against LFA-1 completely inhibits HIV-mediated fusion of uninfected T cell blasts to HIV infected cells. This result indicates that LFA-1 is involved in HIV-induced syncytium formation, a major cytopathic mechanism of the virus.
The LFA-1 molecule, which is expressed on T and B lymphocytes as well as on macrophages, thymocytes, granulocytes, and a subpopulation of bone marrow cells, is composed of two non-covalently associated polypeptides of 175,000 Kd (α; CD11a) and 95,000 Kd (β; CD18). The β-chain of LFA-1 is also common to two other leukocyte antigens: Mac-1 (α-chain 165,000 Kd; CD11b); the type-three complement receptor; and LeuM5 (α-chain 150,000 Kd; CD11c), a molecule possibly associated with type-four complement receptor activity. Although the three α-subunits differ in size, there is evidence suggesting that all three subunits are encoded by a single gene or duplicated genes. cDNA encoding the human β-chain has been cloned and found to be 50% identical in primary structure to the β-chain of integrin, a chick fibroblast fibronectin receptor. These studies and others have shown that molecules of the LFA-1 glycoprotein family are members of the larger arginine-glycine-aspartate (RGD) adhesion family known as integrins.
At present, methods of limited effectiveness exist for the treatment of AIDS or other disorders in which the intercellular interaction of lymphocytes helps to mediate the pathologic state. Those drugs which are administered generally have severe contraindications associated with their use. Consequently, a considerable need exists for a therapeutic agent which can inhibit lymphocytic intercellular interaction in AIDS and other immune response mediated disorders.